The discovery that the methylation of homocysteine is impaired in malignant and embryonic cells but not in normal adult cells in tissue culture has directed our attention to the components of this reaction: the enzyme, N5-methyltetrahydrofolate: homocysteine methyltransferase; the substrates, homocysteine and N5-methyltetrahydrofolate; and the products, methionine and tetrahydrofolate. These metabolites are involved in the pathways of C1 metabolism in general and include reactions involving S-adenosylmethionine, S-adenosylhomocysteine, reduced and methylated-reduced folates (mono- and polyglutamate forms), vitamin B12, and sulfur amino acids. Therapeutically accessible metabolic pathways are evident and are to be investigated by techniques requiring biochemical, histological, tissue culture and animal studies. Methionine deprivation induced by methioninase coupled with homocysteine, vitamin B12 and folate supplementation will be tested on animals with fatal neoplasms. In addition, this regimen has been coupled with already proven modes of treatment of malignant diseases.